@article {817, title = {Metatranscriptomic analysis reveals gut microbiome bacterial genes in pyruvate and amino acid metabolism associated with hyperuricemia and gout in humans.}, journal = {Sci Rep}, volume = {15}, year = {2025}, month = {2025 Mar 22}, pages = {9981}, abstract = {

Several pathologies with metabolic origin, such as hyperuricemia and gout, have been associated with the gut microbiota taxonomic profile. However, there is no evidence of which bacterial genes are being expressed in the gut microbiome, and of their potential effects on hyperuricemia and gout. We sequenced the RNA of 26 fecal samples from 10 healthy normouricemic controls, 10 with asymptomatic hyperuricemia (AH), and six gout patients. The coding sequences were mapped to KEGG orthologues (KO). We compared the expression levels using generalized linear models and validated the expression of four KO in a larger sample by qRT-PCR. A distinct genetic expression pattern was identified among groups. AH individuals and gout patients showed an over-expression of KOs mainly related to pyruvate metabolism (Log2foldchange > 23, p-adj <= 3.56 {\texttimes} 10), the pentose pathway (Log2foldchange > 24, p-adj < 1.10 {\texttimes} 10) and purine metabolism (Log2foldchange > 22, p-adj < 1.25 {\texttimes} 10). AH subjects had lower expression of KO related to glycine metabolism (Log2foldchange=-18, p-adj < 1.72 {\texttimes} 10) than controls. Gout patients had lower expression (Log2foldchange=-22.42, p-adj < 3.31 {\texttimes} 10) of a KO involved in phenylalanine biosynthesis, in comparison to controls and AH subjects. The over-expression seen for the KO related to pyruvate metabolism and the pentose pathway in gout patients{\textasciiacute} microbiome was validated. There is a differential gene expression pattern in the gut microbiome of normouricemic individuals, AH subjects and gout patients. These differences are mainly located in metabolic pathways involved in acetate precursors and bioavailability of amino acids.

}, keywords = {Adult, Aged, Amino Acids, Bacteria, Case-Control Studies, Feces, Female, Gastrointestinal Microbiome, Gene Expression Profiling, Genes, Bacterial, Gout, Humans, Hyperuricemia, Male, Middle Aged, Pyruvic Acid, Transcriptome}, issn = {2045-2322}, doi = {10.1038/s41598-025-93899-1}, author = {Mart{\'\i}nez-Nava, Gabriela Ang{\'e}lica and Altamirano-Molina, Efren and V{\'a}zquez-Mellado, Janitzia and Casimiro-Soriguer, Carlos S and Dopazo, Joaquin and Lozada-P{\'e}rez, Carlos and Herrera-L{\'o}pez, Br{\'\i}gida and Mart{\'\i}nez-G{\'o}mez, Laura Edith and Mart{\'\i}nez-Armenta, Carlos and Guido-G{\'o}mora, Dafne Lissete and Valle-Guti{\'e}rrez, Sarah{\'\i} and Suarez-Ahedo, Carlos and Camacho-Rea, Mar{\'\i}a Del Carmen and Mart{\'\i}nez-Garc{\'\i}a, Mireya and Guti{\'e}rrez-Esparza, Guadalupe and Amezcua-Guerra, Luis M and Zamudio-Cuevas, Yessica and Mart{\'\i}nez-Flores, Karina and Fern{\'a}ndez-Torres, Javier and Burguete-Garc{\'\i}a, Ana I and Orbe-Orihuela, Yaneth Citlalli and Lagunas-Mart{\'\i}nez, Alfredo and M{\'e}ndez-Salazar, Eder Orlando and Francisco-Balderas, Adriana and Palacios-Gonz{\'a}lez, Berenice and Pineda, Carlos and L{\'o}pez-Reyes, Alberto} } @article {814, title = {Aripiprazole as protector against COVID-19 mortality.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 May 29}, pages = {12362}, abstract = {

The relation of antipsychotics with severe Coronavirus Disease 19 (COVID-19) outcomes is a matter of debate since the beginning of the pandemic. To date, controversial results have been published on this issue. We aimed to prove whether antipsychotics might exert adverse or protective effects against fatal outcomes derived from COVID-19. A population-based retrospective cohort study (January 2020 to November 2020) comprising inpatients (15,968 patients) who were at least 18~years old and had a laboratory-confirmed COVID-19 infection. Two sub-cohorts were delineated, comprising a total of 2536 inpatients: individuals who either had no prescription medication or were prescribed an antipsychotic within the 15~days preceding hospitalization. We conducted survival and odds ratio analyses to assess the association between antipsychotic use and mortality, reporting both unadjusted and covariate-adjusted results. We computed the average treatment effects, using the untreated group as the reference, and the average treatment effect on the treated, focusing solely on the antipsychotic-treated population. Among the eight antipsychotics found to be in use, only aripiprazole showed a significant decrease in the risk of death from COVID-19 [adjusted odds ratio (OR) = 0.86; 95\% CI, 0.79-0.93, multiple-testing adjusted p-value < 0.05]. Importantly, these findings were consistent for both covariate-adjusted and unadjusted analyses. Aripiprazole has been shown to have a differentiated beneficial effect in protecting against fatal clinical outcome in COVID-19 infected individuals. We speculate that the differential effect of aripiprazole on controlling immunological pathways and inducible inflammatory enzymes, that are critical in COVID19 illness, may be associated with our findings herein.

}, keywords = {Adult, Aged, Aged, 80 and over, Antipsychotic Agents, Aripiprazole, COVID-19, COVID-19 Drug Treatment, Female, Humans, Male, Middle Aged, Retrospective Studies, SARS-CoV-2}, issn = {2045-2322}, doi = {10.1038/s41598-024-60297-y}, author = {Loucera-Mu{\~n}ecas, C and Canal-Rivero, M and Ruiz-Veguilla, M and Carmona, R and Bostelmann, G and Garrido-Torres, N and Dopazo, J and Crespo-Facorro, B} } @article {811, title = {Genotypic characterization and antimicrobial susceptibility of human isolates in Southern Spain.}, journal = {Microbiol Spectr}, volume = {12}, year = {2024}, month = {2024 Oct 03}, pages = {e0102824}, abstract = {

is the main cause of bacterial gastroenteritis and a public health problem worldwide. Little information is available on the genotypic characteristics of human in Spain. This study is based on an analysis of the resistome, virulome, and phylogenetic relationship, antibiogram prediction, and antimicrobial susceptibility of 114 human isolates of from a tertiary hospital in southern Spain from October 2020 to June 2023. The isolates were sequenced using Illumina technology, and a bioinformatic analysis was subsequently performed. The susceptibility of isolates to ciprofloxacin, tetracycline, and erythromycin was also tested. The resistance rates for each antibiotic were 90.3\% for ciprofloxacin, 66.7\% for tetracycline, and 0.88\% for erythromycin. The fluoroquinolone resistance rate obtained is well above the European average (69.1\%). CC-21 ( = 23), ST-572 ( = 13), and ST-6532 ( = 13) were the most prevalent clonal complexes (CCs) and sequence types (STs). In the virulome, the , and genes were detected in all the isolates. A prevalence of 20.1\% was obtained for the genes and , which are related to the pathogenesis of Guillain-Barr{\'e} syndrome (GBS). The prevalence of the main antimicrobial resistance markers detected were CmeABC (92.1\%), RE-cmeABC (7.9\%), the T86I substitution in (88.9\%), (72.6\%) (65.8\%), and (17.1\%). High antibiogram prediction rates (>97\%) were obtained, except for in the case of the erythromycin-resistant phenotype. This study contributes significantly to the knowledge of genomics for the prevention, treatment, and control of infections caused by this pathogen.IMPORTANCEDespite being the pathogen with the greatest number of gastroenteritis cases worldwide, remains a poorly studied microorganism. A sustained increase in fluoroquinolone resistance in human isolates is a problem when treating infections. The development of whole genome sequencing (WGS) techniques has allowed us to better understand the genotypic characteristics of this pathogen and relate them to antibiotic resistance phenotypes. These techniques complement the data obtained from the phenotypic analysis of isolates. The zoonotic transmission of through the consumption of contaminated poultry supports approaching the study of this pathogen through "One Health" approach. In addition, due to the limited information on the genomic characteristics of in Spain, this study provides important data and allows us to compare the results with those obtained in other countries.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents, Campylobacter Infections, Campylobacter jejuni, Child, Child, Preschool, Ciprofloxacin, Drug Resistance, Bacterial, Erythromycin, Female, Genotype, Humans, Infant, Male, Microbial Sensitivity Tests, Middle Aged, Phylogeny, Spain, Tetracycline, Young Adult}, issn = {2165-0497}, doi = {10.1128/spectrum.01028-24}, author = {Fern{\'a}ndez-Palacios, Pablo and Gal{\'a}n-S{\'a}nchez, F{\'a}tima and Casimiro-Soriguer, Carlos S and Jurado-Tarifa, Estefan{\'\i}a and Arroyo, Federico and Lara, Mar{\'\i}a and Chaves, J Alberto and Dopazo, Joaquin and Rodriguez-Iglesias, Manuel A} } @article {812, title = {Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).}, journal = {J Med Genet}, volume = {61}, year = {2024}, month = {2024 Sep 24}, pages = {927-934}, abstract = {

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in and genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.

METHODS: Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.

RESULTS: Both patients harbouring low-risk GISTs with different mutations ( and ) shared homozygous germline pathogenic deletions in both and genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as . No particular pathogenic SNV shared by both patients was detected.

CONCLUSION: Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, and deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

}, keywords = {DNA Copy Number Variations, Female, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-kit, Receptor, Platelet-Derived Growth Factor alpha, Whole Genome Sequencing}, issn = {1468-6244}, doi = {10.1136/jmg-2024-110109}, author = {Moura, David S and L{\'o}pez L{\'o}pez, Daniel and di Lernia, Davide and Martin-Ruiz, Marta and Lopez-Alvarez, Maria and Ramos, Rafael and Merino, Jose and Dopazo, Joaquin and Lopez-Guerrero, Jose and Mondaza-Hernandez, Jose L and Romero, Pablo and Hindi, Nadia and Garcia-Foncillas, Jesus and Martin-Broto, Javier} } @article {707, title = {Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.}, journal = {J Immunother Cancer}, volume = {8}, year = {2020}, month = {2020 11}, abstract = {

BACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48\% (95\% CI 41\% to 55\%). The most common grade 3-4 adverse events included transaminitis (17.3\%) and neutropenia (11.5\%).

CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.

}, keywords = {Adult, Aged, Antineoplastic Agents, Immunological, Female, Humans, Male, Middle Aged, Nivolumab, Sarcoma, Sunitinib, Young Adult}, issn = {2051-1426}, doi = {10.1136/jitc-2020-001561}, author = {Martin-Broto, Javier and Hindi, Nadia and Grignani, Giovanni and Martinez-Trufero, Javier and Redondo, Andres and Valverde, Claudia and Stacchiotti, Silvia and Lopez-Pousa, Antonio and D{\textquoteright}Ambrosio, Lorenzo and Gutierrez, Antonio and Perez-Vega, Herminia and Encinas-Tobajas, Victor and de Alava, Enrique and Collini, Paola and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Carrasco-Garcia, Irene and Lopez-Alvarez, Maria and Moura, David S and Lopez-Martin, Jose A} } @article {653, title = {Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.}, journal = {Lancet Oncol}, volume = {21}, year = {2020}, month = {2020 03}, pages = {456-466}, abstract = {

BACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged >=18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.

FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58\%) of 31 patients had a partial response, 12 (39\%) had stable disease, and one (3\%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58\% (95\% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53\%] of 34 patients), fatigue (17 [50\%]), and hypertension (17 [50\%]).

INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

}, keywords = {Aged, Female, Follow-Up Studies, Humans, Indazoles, Male, Middle Aged, Neoplasm Metastasis, Prognosis, Prospective Studies, Protein Kinase Inhibitors, Pyrimidines, Response Evaluation Criteria in Solid Tumors, Solitary Fibrous Tumors, Sulfonamides, Survival Rate}, issn = {1474-5488}, doi = {10.1016/S1470-2045(19)30826-5}, author = {Martin-Broto, Javier and Cruz, Josefina and Penel, Nicolas and Le Cesne, Axel and Hindi, Nadia and Luna, Pablo and Moura, David S and Bernabeu, Daniel and de Alava, Enrique and Lopez-Guerrero, Jose Antonio and Dopazo, Joaquin and Pe{\~n}a-Chilet, Maria and Gutierrez, Antonio and Collini, Paola and Karanian, Marie and Redondo, Andres and Lopez-Pousa, Antonio and Grignani, Giovanni and Diaz-Martin, Juan and Marcilla, David and Fernandez-Serra, Antonio and Gonzalez-Aguilera, Cristina and Casali, Paolo G and Blay, Jean-Yves and Stacchiotti, Silvia} } @article {554, title = {Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.}, journal = {Br J Dermatol}, volume = {181}, year = {2019}, month = {2019 09}, pages = {512-522}, abstract = {

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in~situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What{\textquoteright}s already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

}, keywords = {Adolescent, Adult, Biopsy, Blister, Case-Control Studies, Cells, Cultured, Child, Child, Preschool, Epidermolysis Bullosa, Epidermolysis Bullosa Dystrophica, Extracellular Matrix, Extracellular Matrix Proteins, Female, Fibroblasts, Fibrosis, Gene Expression Regulation, Healthy Volunteers, Humans, Infant, Infant, Newborn, Male, Middle Aged, mutation, Periodontal Diseases, Photosensitivity Disorders, Primary Cell Culture, RNA-seq, Skin, Xeroderma Pigmentosum, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.17698}, author = {Chac{\'o}n-Solano, E and Le{\'o}n, C and D{\'\i}az, F and Garc{\'\i}a-Garc{\'\i}a, F and Garc{\'\i}a, M and Esc{\'a}mez, M J and Guerrero-Aspizua, S and Conti, C J and Menc{\'\i}a, {\'A} and Mart{\'\i}nez-Santamar{\'\i}a, L and Llames, S and P{\'e}vida, M and Carbonell-Caballero, J and Puig-Butill{\'e}, J A and Maseda, R and Puig, S and de Lucas, R and Baselga, E and Larcher, F and Dopazo, J and Del Rio, M} } @article {423, title = {Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.}, journal = {Lancet Oncol}, volume = {20}, year = {2019}, month = {2019 Jan}, pages = {134-144}, abstract = {

BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged >= 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51\%) of 35 evaluable patients had partial responses, nine (26\%) had stable disease, and eight (23\%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51\% (95\% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29\%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31\%] of 36 patients), neutropenia (four [11\%]), increased concentrations of alanine aminotransferase (four [11\%]), and increased concentrations of bilirubin (three [8\%]).

INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

}, keywords = {Adult, Aged, Angiogenesis Inhibitors, Antineoplastic Agents, Female, Humans, Indazoles, Male, Middle Aged, Multivariate Analysis, Pyrimidines, Response Evaluation Criteria in Solid Tumors, Soft Tissue Neoplasms, Solitary Fibrous Tumors, Sulfonamides, Survival Analysis}, issn = {1474-5488}, doi = {10.1016/S1470-2045(18)30676-4}, author = {Martin-Broto, Javier and Stacchiotti, Silvia and Lopez-Pousa, Antonio and Redondo, Andres and Bernabeu, Daniel and de Alava, Enrique and Casali, Paolo G and Italiano, Antoine and Gutierrez, Antonio and Moura, David S and Pe{\~n}a-Chilet, Maria and Diaz-Martin, Juan and Biscuola, Michele and Taron, Miguel and Collini, Paola and Ranchere-Vince, Dominique and Garcia Del Muro, Xavier and Grignani, Giovanni and Dumont, Sarah and Martinez-Trufero, Javier and Palmerini, Emanuela and Hindi, Nadia and Sebio, Ana and Dopazo, Joaquin and Dei Tos, Angelo Paolo and LeCesne, Axel and Blay, Jean-Yves and Cruz, Josefina} } @article {407, title = {The modular network structure of the mutational landscape of Acute Myeloid Leukemia.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0202926}, abstract = {

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50\% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

}, keywords = {Adult, Aged, Cytodiagnosis, Exome Sequencing, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Heterogeneity, Humans, Karyotype, Leukemia, Myeloid, Acute, Male, Middle Aged, mutation, Neoplasm Proteins, Nucleophosmin, Prognosis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0202926}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Such, Esperanza and Garc{\'\i}a-Alonso, Luz and Liquori, Alessandro and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Alonso, Carmen and Barrag{\'a}n, Eva and G{\'o}mez-Segu{\'\i}, In{\'e}s and Neef, Alexander and Herv{\'a}s, David and Montesinos, Pau and Sanz, Guillermo and Sanz, Miguel Angel and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {384, title = {Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis.}, journal = {Oncotarget}, volume = {8}, year = {2017}, month = {2017 Feb 14}, pages = {11589-11599}, abstract = {

The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.

}, keywords = {Adult, Coculture Techniques, Computational Biology, gene expression, Genetic Predisposition to Disease, Genomics, Hair Color, Humans, Keratinocytes, Melanocytes, Middle Aged, Phenotype, Receptor, Melanocortin, Type 1}, issn = {1949-2553}, doi = {10.18632/oncotarget.14140}, url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget\&page=article\&op=view\&path\%5B\%5D=14140\&path\%5B\%5D=45094}, author = {Puig-Butille, Joan Anton and Gimenez-Xavier, Pol and Visconti, Alessia and Nsengimana, J{\'e}r{\'e}mie and Garcia-Garcia, Francisco and Tell-Marti, Gemma and Escamez, Maria Jos{\'e} and Newton-Bishop, Julia and Bataille, Veronique and Del Rio, Marcela and Dopazo, Joaquin and Falchi, Mario and Puig, Susana} } @article {386, title = {GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 May 04}, pages = {1794-1795}, keywords = {Aged, Amino Acid Sequence, Bone Density Conservation Agents, Dimethylallyltranstransferase, Diphosphonates, Exome, Farnesyltranstransferase, Female, Femoral Fractures, Geranyltranstransferase, Humans, Middle Aged, mutation}, issn = {1533-4406}, doi = {10.1056/NEJMc1612804}, url = {http://www.nejm.org/doi/full/10.1056/NEJMc1612804}, author = {Roca-Ayats, Neus and Balcells, Susana and Garcia-Giralt, Nat{\`a}lia and Falc{\'o}-Mascar{\'o}, Maite and Mart{\'\i}nez-Gil, N{\'u}ria and Abril, Josep F and Urreizti, Roser and Dopazo, Joaquin and Quesada-G{\'o}mez, Jos{\'e} M and Nogu{\'e}s, Xavier and Mellibovsky, Leonardo and Prieto-Alhambra, Daniel and Dunford, James E and Javaid, Muhammad K and Russell, R Graham and Grinberg, Daniel and D{\'\i}ez-P{\'e}rez, Adolfo} } @article {561, title = {Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns.}, journal = {Transl Psychiatry}, volume = {6}, year = {2016}, month = {2016 Jan 19}, pages = {e718}, abstract = {

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer{\textquoteright}s disease, dementia with Lewy bodies, Parkinson{\textquoteright}s disease and Alzheimer-like neurodegenerative profile associated with Down{\textquoteright}s syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.

}, keywords = {Adult, Aged, Aged, 80 and over, DNA Methylation, Epigenomics, Female, Humans, Male, Middle Aged, neurodegenerative diseases, Prefrontal Cortex, Tissue Array Analysis}, issn = {2158-3188}, doi = {10.1038/tp.2015.214}, author = {Sanchez-Mut, J V and Heyn, H and Vidal, E and Moran, S and Sayols, S and Delgado-Morales, R and Schultz, M D and Ansoleaga, B and Garcia-Esparcia, P and Pons-Espinal, M and de Lagran, M M and Dopazo, J and Rabano, A and Avila, J and Dierssen, M and Lott, I and Ferrer, I and Ecker, J R and Esteller, M} } @article {437, title = {Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 Oct 13}, pages = {35370}, abstract = {

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

}, keywords = {Aged, Animals, Co-Repressor Proteins, Codon, Nonsense, Cohort Studies, Comparative Genomic Hybridization, Consanguinity, DNA Mutational Analysis, Exome, Eye Proteins, Female, Gene Expression Regulation, Genes, Recessive, Homeodomain Proteins, Homozygote, Humans, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Protein Interaction Mapping, Retina, Retinal Dystrophies, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Spain, Trans-Activators, Transcription Factors}, issn = {2045-2322}, doi = {10.1038/srep35370}, author = {Corton, M and Avila-Fern{\'a}ndez, A and Campello, L and S{\'a}nchez, M and Benavides, B and L{\'o}pez-Molina, M I and Fern{\'a}ndez-S{\'a}nchez, L and S{\'a}nchez-Alcudia, R and da Silva, L R J and Reyes, N and Mart{\'\i}n-Garrido, E and Zurita, O and Fern{\'a}ndez-San Jos{\'e}, P and P{\'e}rez-Carro, R and Garc{\'\i}a-Garc{\'\i}a, F and Dopazo, J and Garc{\'\i}a-Sandoval, B and Cuenca, N and Ayuso, C} } @article {449, title = {Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Jan}, pages = {62-72}, abstract = {

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

}, keywords = {Adult, Aged, Animals, Axons, Charcot-Marie-Tooth Disease, Female, gene expression, Humans, Infant, Male, Mice, Middle Aged, mutation, Pedigree, Phenotype, Sciatic Nerve, Sural Nerve, Transcription Factors, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awv311}, author = {Sevilla, Teresa and Lupo, Vincenzo and Mart{\'\i}nez-Rubio, Dolores and Sancho, Paula and Sivera, Rafael and Chumillas, Mar{\'\i}a J and Garc{\'\i}a-Romero, Mar and Pascual-Pascual, Samuel I and Muelas, Nuria and Dopazo, Joaquin and V{\'\i}lchez, Juan J and Palau, Francesc and Espin{\'o}s, Carmen} } @article {445, title = {Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer.}, journal = {Oncotarget}, volume = {7}, year = {2016}, month = {2016 Mar 15}, pages = {12904-16}, abstract = {

Lung cancer (LC) is responsible for most cancer deaths. One of the main factors contributing to the lethality of this disease is the fact that a large proportion of patients are diagnosed at advanced stages when a clinical intervention is unlikely to succeed. In this study, we evaluated the potential of metabolomics by 1H-NMR to facilitate the identification of accurate and reliable biomarkers to support the early diagnosis and prognosis of non-small cell lung cancer (NSCLC).We found that the metabolic profile of NSCLC patients, compared with healthy individuals, is characterized by statistically significant changes in the concentration of 18 metabolites representing different amino acids, organic acids and alcohols, as well as different lipids and molecules involved in lipid metabolism. Furthermore, the analysis of the differences between the metabolic profiles of NSCLC patients at different stages of the disease revealed the existence of 17 metabolites involved in metabolic changes associated with disease progression.Our results underscore the potential of metabolomics profiling to uncover pathophysiological mechanisms that could be useful to objectively discriminate NSCLC patients from healthy individuals, as well as between different stages of the disease.

}, keywords = {Adult, Aged, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Disease Progression, Female, Humans, Lung Neoplasms, Male, metabolomics, Middle Aged, Proton Magnetic Resonance Spectroscopy}, issn = {1949-2553}, doi = {10.18632/oncotarget.7354}, author = {Puchades-Carrasco, Leonor and Jantus-Lewintre, Eloisa and P{\'e}rez-Rambla, Clara and Garcia-Garcia, Francisco and Lucas, Rut and Calabuig, Silvia and Blasco, Ana and Dopazo, Joaquin and Camps, Carlos and Pineda-Lucena, Antonio} } @article {458, title = {Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.}, journal = {Gene}, volume = {571}, year = {2015}, month = {2015 Oct 15}, pages = {52-7}, abstract = {

FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.

}, keywords = {Adult, Aged, Female, Fragile X Mental Retardation Protein, Fragile X Syndrome, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene ontology, Genome-Wide Association Study, Heterozygote, Humans, Middle Aged, Models, Genetic, mutation, Oligonucleotide Array Sequence Analysis, Oocytes, Primary Ovarian Insufficiency, Signal Transduction}, issn = {1879-0038}, doi = {10.1016/j.gene.2015.06.039}, author = {Alvarez-Mora, M I and Rodriguez-Revenga, L and Madrigal, I and Garc{\'\i}a-Garc{\'\i}a, F and Duran, M and Dopazo, J and Estivill, X and Mil{\`a}, M} } @article {456, title = {The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.}, journal = {Eur J Neurol}, volume = {22}, year = {2015}, month = {2015 Dec}, pages = {1548-55}, abstract = {

BACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.

METHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays.

RESULTS: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.

CONCLUSIONS: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.

}, keywords = {Adult, Aged, Aged, 80 and over, Axons, Charcot-Marie-Tooth Disease, Early Growth Response Protein 2, Exome, Female, Humans, Male, Middle Aged, mutation, Pedigree, Phenotype, Severity of Illness Index, Young Adult}, issn = {1468-1331}, doi = {10.1111/ene.12782}, author = {Sevilla, T and Sivera, R and Mart{\'\i}nez-Rubio, D and Lupo, V and Chumillas, M J and Calpena, E and Dopazo, J and V{\'\i}lchez, J J and Palau, F and Espin{\'o}s, C} } @article {489, title = {Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e116176}, abstract = {

This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Base Sequence, Child, Chromosome Segregation, DNA Mutational Analysis, Exome, Family, Female, Humans, Inheritance Patterns, Male, Middle Aged, Molecular Sequence Data, mutation, Pedigree, Retinal Dystrophies, Rhodopsin}, issn = {1932-6203}, doi = {10.1371/journal.pone.0116176}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Vela-Boza, Alicia and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {504, title = {Differential gene-expression analysis defines a molecular pattern related to olive pollen allergy.}, journal = {J Biol Regul Homeost Agents}, volume = {27}, year = {2013}, month = {2013 Apr-Jun}, pages = {337-50}, abstract = {

Analysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations.

}, keywords = {Adult, Female, Gene Expression Profiling, Humans, Male, Middle Aged, Olea, Principal Component Analysis, Rhinitis, Allergic, Seasonal}, issn = {0393-974X}, author = {Aguerri, M and Calzada, D and Montaner, D and Mata, M and Florido, F and Quiralte, J and Dopazo, J and Lahoz, C and Cardaba, B} } @article {507, title = {Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.}, journal = {Clin Chim Acta}, volume = {421}, year = {2013}, month = {2013 Jun 05}, pages = {184-90}, abstract = {

BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS.

METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study.

CONCLUSIONS: Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.

}, keywords = {Acute Coronary Syndrome, Acute-Phase Proteins, Adult, biomarkers, Blood Cells, Early Diagnosis, gene expression, Gene Expression Profiling, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Transcriptome}, issn = {1873-3492}, doi = {10.1016/j.cca.2013.03.011}, author = {Silbiger, Vivian N and Luchessi, Andr{\'e} D and Hirata, Ros{\'a}rio D C and Lima-Neto, L{\'\i}dio G and Cavichioli, D{\'e}bora and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Dopazo, Joaquin and Garcia-Garcia, Francisco and Dos Santos, Elizabete S and Ramos, Rui F and Sampaio, Marcelo F and Armaganijan, Dikran and Sousa, Amanda G M R and Hirata, Mario H} } @article {501, title = {Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.}, journal = {Exp Dermatol}, volume = {22}, year = {2013}, month = {2013 Jul}, pages = {494-6}, abstract = {

Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P~=~0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P~=~0.012) and IL-1B (P~=~0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.

}, keywords = {Administration, Topical, Adult, Aged, Aged, 80 and over, Biopsy, Deoxyribodipyrimidine Photo-Lyase, Female, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Homeostasis, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Liposomes, Male, Middle Aged, Muscle Proteins, Phenotype, Phosphoprotein Phosphatases, Reactive Oxygen Species, Skin, Skin Neoplasms, Ultraviolet Rays}, issn = {1600-0625}, doi = {10.1111/exd.12177}, author = {Puig-Butille, Joan Anton and Malvehy, Josep and Potrony, Miriam and Trullas, Carles and Garcia-Garcia, Francisco and Dopazo, Joaquin and Puig, Susana} } @article {547, title = {DNA methylation epigenotypes in breast cancer molecular subtypes.}, journal = {Breast Cancer Res}, volume = {12}, year = {2010}, month = {2010}, pages = {R77}, abstract = {

INTRODUCTION: Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes.

METHODS: Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis.

RESULTS: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.

CONCLUSIONS: Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.

}, keywords = {Aged, Breast Neoplasms, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genes, p53, Genotype, Humans, Ki-67 Antigen, Middle Aged, mutation, Neoplasm Grading, Oligonucleotide Array Sequence Analysis, Receptor, ErbB-2, Tumor Suppressor Protein p53}, issn = {1465-542X}, doi = {10.1186/bcr2721}, author = {Bediaga, Naiara G and Acha-Sagredo, Amelia and Guerra, Isabel and Viguri, Amparo and Albaina, Carmen and Ruiz Diaz, Irune and Rezola, Ricardo and Alberdi, Maria Jesus and Dopazo, Joaquin and Montaner, David and Renobales, Mertxe and Fernandez, Agustin F and Field, John K and Fraga, Mario F and Liloglou, Triantafillos and de Pancorbo, Marian M} } @article {597, title = {Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information.}, journal = {Oncogene}, volume = {27}, year = {2008}, month = {2008 Mar 06}, pages = {1554-61}, abstract = {

Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95\%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

}, keywords = {Adenoma, Adolescent, Adult, Aged, Biomarkers, Tumor, Carcinoma, Carcinoma, Papillary, Cell Differentiation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, RNA, Neoplasm, Signal Transduction, Thyroid Neoplasms}, issn = {1476-5594}, doi = {10.1038/sj.onc.1210792}, author = {Montero-Conde, C and Mart{\'\i}n-Campos, J M and Lerma, E and Gimenez, G and Mart{\'\i}nez-Guitarte, J L and Combal{\'\i}a, N and Montaner, D and Mat{\'\i}as-Guiu, X and Dopazo, J and de Leiva, A and Robledo, M and Mauricio, D} }